Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids.

We report a practical and sustainable electrophotochemical metal-catalyzed protocol for decarboxylative cyanation of simple aliphatic carboxylic acids. This environmentally friendly method features easy availability of substrates, broad functional group compatibility, and directly converts a diverse range of aliphatic carboxylic acids including primary and tertiary alkyl acids into synthetically versatile alkylnitriles without using chemical oxidants or costly cyanating reagents under mild reaction conditions.

Thermally induced changes in the profiles of phytocannabinoids and other bioactive compounds in Cannabis sativa L. inflorescences.

Phytocannabinoids occurring in Cannabis Sativa L. are unique secondary metabolites possessing interesting pharmacological activities. In this study, the dynamics of thermally induced (60 and 120 °C) phytocannabinoid reactions in four cannabis varieties were investigated. Using UHPLC-HRMS/MS, 40 phytocannabinoids were involved in target analysis, and an additional 281 compounds with cannabinoid-like structures and 258 non-cannabinoid bioactive compounds were subjected to suspect screening. As expected, the key reaction was the decarboxylation of acidic phytocannabinoids. Nevertheless, the rate constants differed among cannabis varieties, documenting the matrix-dependence of this process. Besides neutral counterparts of acidic species, ́new bioactive compounds such as hydroxyquinones were found in heated samples. In addition, changes in other bioactive compounds with both cannabinoid-like and non-cannabinoid structures were documented during cannabis heating at 120 °C. The data document the complexity of heat-induced processes and provide a further understanding of changes in bioactivities occurring under such conditions.

The iron(III) coordinating properties of citrate and α-hydroxycarboxylate containing siderophores.

The iron(III) binding properties of citrate and rhizoferrin, a citrate containing siderophore, are compared. Citrate forms many oligonuclear complexes, whereas rhizoferrin forms a single mononuclear complex. The α-hydroxycarboxylate functional group, which is present in both citrate, and rhizoferrin, has a high affinity and selectivity for iron(III) under most biological conditions. The nature of the toxic form of iron found in the blood of patients suffering from many haemoglobinopathies and haemochromatosis is identified as a mixture of iron(III)citrate complexes. The significance of the presence of this iron pool to patients suffering from systemic iron overload is discussed. The wide utilisation of the α-hydroxycarboxylate functional group in siderophore structures is described, as is their photo-induced decarboxylation leading to the release of iron(II) ions. The importance of this facile dissociation to algal iron uptake is discussed.

Multimodal Acridine Photocatalysis Enables Direct Access to Thiols from Carboxylic Acids and Elemental Sulfur.

Development of photocatalytic systems that facilitate mechanistically divergent steps in complex catalytic manifolds by distinct activation modes can enable previously inaccessible synthetic transformations. However, multimodal photocatalytic systems remain understudied, impeding their implementation in catalytic methodology. We report herein a photocatalytic access to thiols that directly merges the structural diversity of carboxylic acids with the ready availability of elemental sulfur without substrate preactivation. The photocatalytic transformation provides a direct radical-mediated segue to one of the most biologically important and synthetically versatile organosulfur functionalities, whose synthetic accessibility remains largely dominated by two-electron-mediated processes based on toxic and uneconomical reagents and precursors. The two-phase radical process is facilitated by a multimodal catalytic reactivity of acridine photocatalysis that enables both the singlet excited state PCET-mediated decarboxylative carbon-sulfur bond formation and the previously unknown radical reductive disulfur bond cleavage by a photoinduced HAT process in the silane-triplet acridine system. The study points to a significant potential of multimodal photocatalytic systems in providing unexplored directions to previously inaccessible transformations.

Graphitic Carbon Nitride as a Photocatalyst for Decarboxylative C(sp2)-C(sp3) Couplings via Nickel Catalysis.

The development of robust and reliable methods for the construction of C(sp2)-C(sp3) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photocatalysts based on precious-metals due to their efficient redox processes and tuneable properties. However, due to the cost, scarcity, and toxicity of these metals, the search for suitable replacements should be a priority. Here, we show the use of commercially available heterogeneous semiconductor graphitic carbon nitride (gCN) as a photocatalyst, combined with nickel catalysis, for the cross-coupling between aryl halide and carboxylic acid coupling partners. gCN has been shown to engage in single-electron-transfer (SET) and energy-transfer (EnT) processes for the formation of C-X bonds, and in this manuscript we overcome previous limitations to furnish C-C over C-O bonds using carboxylic acids. A broad scope of both aryl halides and carboxylic acids is presented, and recycling of the photocatalyst demonstrated. The mechanism of the reaction is also investigated.

Acid-catalyzed transformation of orange waste into furfural: the effect of pectin degree of esterification.

The transformation of biomasses from agro-industrial waste can significantly impact the production of green chemicals from sustainable resources. Pectin is a biopolymer present in lignocellulosic biomass as Orange Peel Waste (OPW) and has possibilities for making platform compounds such as furfural for sustainable chemistry. In this work, we studied the transformation to furfural of OPW, pectins, and D-galacturonic acid (D-GalA), which is the main component (65 wt%) of pectin. We analyzed pectins with different degrees of esterification (45, 60 and 95 DE) in a one-pot hydrolysis reaction system and studied the differences in depolymerization and dehydration of the carbohydrates. The results show that the production of furfural decreases as the DE value increases. Specifically, low DE values favor the formation of furfural since the decarboxylation reaction is favored over deesterification. Interestingly, the furfural concentration is dependent upon the polysaccharide composition of pentoses and uronic acid. The obtained concentrations of furfural (13 and 14 mmol/L), D-xylose (6.2 and 10 mmol/L), and L-arabinose (2.5 and 2.7 mmol/L) remained the same when the galacturonic acid was fed either as a polymer or a monomer under the same reaction conditions (0.01 M SA, 90 min and 433 K). OPW is proposed as a feedstock in a biorefinery, in which on a per kg OPW dry basis, 90 g of pectin and 15 g of furfural were produced in the most favorable case. We conclude that the co-production of pectin and furfural from OPW is economically feasible.

C-Terminal Decarboxylation of Proline-Derived Building Blocks for Protein-Binding Peptides.

Using a set of conformationally restricted Proline-derived Modules (ProMs), our group has recently succeeded in developing inhibitors for the enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain, which is a key mediator of cell migration and plays an important role in tumor metastasis. While these (formally) pentapeptidic compounds show nanomolecular binding affinities towards EVH1, their drug-like properties and cell permeability need to be further optimized before they can be clinically tested as therapeutic agents against metastasis. In this study, we sought to improve these properties by removing the C-terminal carboxylic acid function of our peptoids, either by late-stage decarboxylation or by direct synthesis. For late-stage decarboxylation of ProM-like systems, a method for reductive halo decarboxylation was optimized and applied to several proline-derived substrates. In this way, a series of new decarboxy ProMs suitable as building blocks for decarboxy EVH1 inhibitors were obtained. In addition, we incorporated decarboxy-ProM-1 into the pentapeptide-like compound Ac[2ClF][ProM-2][Decarb-ProM-1], which showed similar affinity towards EVH1 as the methyl ester derivative (Ac[2Cl-F][ProM-2][ProM1]OMe). However, despite better calculated drug-like properties, this compound did not inhibit chemotaxis in a cellular assay.

Iron-Catalyzed, Light-Driven Decarboxylative Alkoxyamination.

An iron-catalyzed visible-light driven decarboxylative alkoxyamination is disclosed. In the presence of FeBr2 and TEMPO, a large array of carboxylic acids including marketed drugs and biobased molecules is turned into the corresponding alkoxyamine derivatives. The versatility of the latter offers an entry towards molecular diversity generation from abundant starting materials and catalyst. Overall, this method proposes a unified and general approach for LMCT-based iron-catalyzed decarboxylative functionalization.

Asymmetric Synthesis of Quaternary α-Aryl Stereocentres in Benzofuran-3(2H)-Ones Using Decarboxylative Asymmetric Allylic Alkylation.

The Pd-catalysed decarboxylative asymmetric allylic alkylation (DAAA) has been applied to the enantioselective synthesis of sterically hindered benzofuran-3(2H)-one-derived α-aryl-ß-keto esters employing the (R,R)-ANDEN phenyl Trost ligand. A range of substrates were synthesised, employing previously developed aryllead triacetate methodology to install various aryl groups. The resulting α-aryl-α-allyl benzofuran-3(2H)-one DAAA products were obtained in moderate to high yields and in enantioselectivities of up to 96 % ee, with the best results observed for substrates containing a di-ortho-substitution pattern on the aryl ring as well as naphthyl-containing substrates.

Decarboxylative Ketonization of Aliphatic Carboxylic Acids in a Continuous Flow Reactor Catalysed by Manganese Oxide on Silica.

The sustainable synthesis of long carbon chain molecules from carbon dioxide, water and electricity relies on the development of waste-free, highly selective C-C bond forming reactions. An example for such a power-to-chemicals process is the industrial-scale fermentation for the production of hexanoic acid. Herein, we describe how this product is transformed into 6-undecanone via decarboxylative ketonization using a heterogeneous manganese oxide/silica catalyst. The reaction reaches full conversion with near-complete selectivity when carried out in a continuous flow reactor, requires no solvent or carrier gas, and releases carbon dioxide and water as the only by-products. The reactor was operated for several weeks with no loss of reactivity, producing 7 kg of 6-undecanone from 10 g of catalyst and achieving a productivity of 1.135 kg per litre of reactor volume per hour. 6-Undecanone and other long-chain ketones accessible this way can be hydrogenated to industrially meaningful alkanes, or converted into valuable fatty acids via a hydrogenation/elimination/isomerizing hydrocarboxylation sequence.

Radical Mediated Decarboxylation of Amino Acids via Photochemical Carbonyl Sulfide (COS) Elimination.

Herein, we present the first examples of amino acid decarboxylation via photochemically activated carbonyl sulfide (COS) elimination of the corresponding thioacids. This method offers a mild approach for the decarboxylation of amino acids, furnishing N-alkyl amino derivatives. The methodology was compatible with amino acids displaying both polar and hydrophobic sidechains and was tolerant towards widely used amino acid-protecting groups. The compatibility of the reaction with continuous-flow conditions demonstrates the scalability of the process.

Direct de/carboxylation of cannabidiolic acid (CBDA) and cannabidiol (CBD) from hemp plant material under supercritical CO2.

Many organic reactions rely on CO2 sources to generate important structural units and valuable chemicals. In this study, we compared the effects of cannabidiol (CBD) and cannabidiolic acid (CBDA) on the supercritical CO2 (scCO2)-induced de/carboxylation reaction. The results showed that CBD was directly carboxylated in the ortho-position to form CBDA with up to 62% conversion. Meanwhile, CBDA decarboxylation occurred on hemp plant material via varying composition. Mechanistic studies revealed that CBD carboxylation was influenced not only by the physical properties of scCO2, but also by the vegetable matrix.

Rhodium-Catalyzed Tandem Asymmetric Allylic Decarboxylative Addition and Cyclization of Vinylethylene Carbonates with N-Nosylimines.

A enantioselective tandem transformation, concerning asymmetric allylic decarboxylative addition and cyclization of N-nosylimines with vinylethylene carbonates (VECs), in the presence of [Rh(C2H4)2Cl]2, chiral sulfoxide-N-olefin tridentate ligand has been developed. The reaction of VECs with various substituted N-nosylimines proceeded smoothly under mild conditions, providing highly functionalized oxazolidine frameworks in good to high yields with good to excellent enantioselectivity.

Peeling the onion: additional layers of regulation in the acid stress response.

Bacteria are capable of withstanding large changes in osmolality and cytoplasmic pH, unlike eukaryotes that tightly regulate their pH and cellular composition. Previous studies on the bacterial acid stress response described a rapid, brief acidification, followed by immediate recovery. More recent experiments with better pH probes have imaged single living cells, and we now appreciate that following acid stress, bacteria maintain an acidic cytoplasm for as long as the stress remains. This acidification enables pathogens to sense a host environment and turn on their virulence programs, for example, enabling survival and replication within acidic vacuoles. Single-cell analysis identified an intracellular pH threshold of ~6.5. Acid stress reduces the internal pH below this threshold, triggering the assembly of a type III secretion system in Salmonella and the secretion of virulence factors in the host. These pathways are significant because preventing intracellular acidification of Salmonella renders it avirulent, suggesting that acid stress pathways represent a potential therapeutic target. Although we refer to the acid stress response as singular, it is actually a complex response that involves numerous two-component signaling systems, several amino acid decarboxylation systems, as well as cellular buffering systems and electron transport chain components, among others. In a recent paper in the Journal of Bacteriology, M. G. Gorelik, H. Yakhnin, A. Pannuri, A. C. Walker, C. Pourciau, D. Czyz, T. Romeo, and P. Babitzke (J Bacteriol 206:e00354-23, 2024, https://doi.org/10.1128/jb.00354-23) describe a new connection linking the carbon storage regulator CsrA to the acid stress response, highlighting new additional layers of complexity.

Electro/Ni Dual-Catalyzed Decarboxylative C(sp3)-C(sp2) Cross-Coupling Reactions of Carboxylates and Aryl Bromide.

Paired redox-neutral electrolysis offers an attractive green platform for organic synthesis by avoiding sacrificial oxidants and reductants. Carboxylates are non-toxic, stable, inexpensive, and widely available, making them ideal nucleophiles for C-C cross-coupling reactions. Here, we report the electro/Ni dual-catalyzed redox-neutral decarboxylative C(sp3)-C(sp2) cross-coupling reactions of pristine carboxylates with aryl bromides. At a cathode, a NiII(Ar)(Br) intermediate is formed through the activation of Ar-Br bond by a NiI-bipyridine catalyst and subsequent reduction. At an anode, the carboxylates, including amino acid, benzyl carboxylic acid, and 2-phenoxy propionic acid, undergo oxidative decarboxylation to form carbon-based free radicals. The combination of NiII(Ar)(Br) intermediate and carbon radical results in the formation of C(sp3)-C(sp2) cross-coupling products. The adaptation of this electrosynthesis method to flow synthesis and valuable molecule synthesis was demonstrated. The reaction mechanism was systematically studied through electrochemical voltammetry and density functional theory (DFT) computational studies. The relationships between the electrochemical properties of carboxylates and the reaction selectivity were revealed. The electro/Ni dual-catalyzed cross-coupling reactions described herein expand the chemical space of paired electrochemical C(sp3)-C(sp2) cross-coupling and represent a promising method for the construction of the C(sp3)-C(sp2) bonds because of the ubiquitous carboxylate nucleophiles and the innate scalability and flexibility of electrochemical flow-synthesis technology.

Computational-aided analysis of the pathway and mechanism of dichloroacetonitrile formation from phenylalanine upon chloramination.

Dichloroacetonitrile (DCAN) is an emerging disinfection by-product (DBP) that is widespread in drinking water. However, the pathway for DCAN formation from aromatic amino acids remains unclear, leading to a lack of an understanding of its explicit fate during chloramination. In this study, we investigated the specific formation mechanism of DCAN during the chloramination of phenylalanine based on reaction kinetics and chemical thermodynamics. The reason for differences between aldehyde and decarboxylation pathways was explained, and kinetic parameters of the pathways were obtained through quantum chemistry calculations. The results showed that the reaction rate constant of the rate-limiting step of the aldehyde pathway with 1.9 × 10-11 s-1 was significantly higher than that of decarboxylation (3.6 × 10-16 s-1 M-1), suggesting that the aldehyde pathway is the main reaction pathway for DCAN formation during the chloramination of phenylalanine to produce DCAN. Subsequently, theoretical calculations were performed to elucidate the effect of pH on the formation mechanism, which aligned well with the experimental results. Dehydrohalogenation was found to be the rate-limiting step under acidic conditions with reaction rate constants higher than those of the rate-limiting step (expulsion of amines) under neutral conditions, increasing the rate of DCAN formation. This study highlights the differences in DCAN formation between the decarboxylation and aldehyde pathways during the chloramination of precursors at both molecular and kinetic levels, contributing to a comprehensive understanding of the reaction mechanisms by which aromatic free amino acids generate DCAN.

Efficient Capture of Cannabis Terpenes in Olive Oil during Microwave-Assisted Cannabinoid Decarboxylation.

The development of selective extraction protocols for Cannabis-inflorescence constituents is still a significant challenge. The characteristic Cannabis fragrance can be mainly ascribed to monoterpenes, sesquiterpenes and oxygenated terpenoids. This work investigates the entrapment of Cannabis terpenes in olive oil from inflorescences via stripping under mild vacuum during the rapid microwave-assisted decarboxylation of cannabinoids (MW, 120 °C, 30 min) and after subsequent extraction of cannabinoids (60 and 100 °C). The profiles of the volatiles collected in the oil samples before and after the extraction step were evaluated using static headspace solid-phase microextraction (HS-SPME), followed by gas chromatography coupled to mass spectrometry (GC-MS). Between the three fractions obtained, the first shows the highest volatile content (~37,400 mg/kg oil), with α-pinene, ß-pinene, ß-myrcene, limonene and trans-ß-caryophyllene as the main components. The MW-assisted extraction at 60 and 100 °C of inflorescences using the collected oil fractions allowed an increase of 70% and 86% of total terpene content, respectively. Considering the initial terpene amount of 91,324.7 ± 2774.4 mg/kg dry inflorescences, the percentage of recovery after decarboxylation was close to 58% (mainly monoterpenes), while it reached nearly 100% (including sesquiterpenes) after extraction. The selective and efficient extraction of volatile compounds, while avoiding direct contact between the matrix and extraction solvents, paves the way for specific applications in various aromatic plants. In this context, aromatized extracts can be employed to create innovative Cannabis-based products within the hemp processing industry, as well as in perfumery, cosmetics, dietary supplements, food, and the pharmaceutical industry.

Selective Electrochemical Modification and Degradation of Polymers.

We demonstrate that electrochemical-induced decarboxylation enables reliable post-polymerization modification and degradation of polymers. Polymers containing N-(acryloxy)phthalimides were subjected to electrochemical decarboxylation under mild conditions, which led to the formation of transient alkyl radicals. By installing these redox-active units, we systematically modified the pendent groups and chain ends of polyacrylates. This approach enabled the production of poly(ethylene-co-methyl acrylate) and poly(propylene-co-methyl acrylate) copolymers, which are difficult to synthesize by direct polymerization. Spectroscopic and chromatographic techniques reveal these transformations are near-quantitative on several polymer systems. Electrochemical decarboxylation also enables the degradation of all-methacrylate poly(N-(methacryloxy)phthalimide-co-methyl methacrylate) copolymers with a degradation efficiency of >95 %. Chain cleavage is achieved through the decarboxylation of the N-hydroxyphthalimide ester and subsequent ß-scission of the backbone radical. Electrochemistry is thus shown to be a powerful tool in selective polymer transformations and controlled macromolecular degradation.

Photoinduced Decarboxylative Radical Phosphinylation.

Reported herein is an unprecedented protocol for C(sp3 )-phosphinylation. With 1 mol % 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) as the catalyst, the visible light induced reaction of redox-active esters of aliphatic carboxylic acids with dimethyl arylphosphonites or diethyl alkylphosphonites at room temperature provides the corresponding decarboxylative phosphinylation products in satisfactory yields. The protocol exhibits broad substrate scope and wide functional-group compatibility, enabling the late-stage modification of complex molecules and rapid synthesis of bioactive phosphinic acids such as glutamine synthetase phosphinothricin and a kynureninase inhibitor. A radical-polar crossover mechanism involving the formation and subsequent oxidation of phosphoranyl radicals followed by nucleophilic demethylation (or deethylation) is proposed.

(De)carboxylation mechanisms of heteroaromatic substrates catalyzed by prenylated FMN-dependent UbiD decarboxylases: An in-silico study.

The UbiD enzymes are proposed to catalyze reversible (de)carboxylation reaction of unsaturated carboxylic acids using prenylated flavin mononucleotide (prFMN) as a cofactor. This positions UbiD enzymes as promising candidates for converting CO2 into valuable chemicals. However, their industrial-scale biotransformation is currently constrained by low conversion rates attributed to thermodynamic limitations. To enhance the carboxylation activity of UbiD enzymes, a molecular-level understanding of the (de)carboxylation mechanisms is necessary. In this study, we investigated the reaction mechanisms of heteroaromatic substrates catalyzed by PtHmfF, PaHudA, and AnlnD enzymes using molecular dynamics (MD) simulations and free energy calculations. Our extensive mechanistic study elucidates the mechanisms involved in the formation of the initial prFMN-substrate intermediate. Specifically, we observed nucleophilic attack during decarboxylation, while carboxylation reactions involving furoic acid, pyrrole, and indole tend to favor a 1,3-dipolar cycloaddition mechanism. Furthermore, we identified proton transfer as the rate-limiting step in the carboxylation reaction. In addition, we considered the perspectives of reaction energies and electron transfer to understand the distinct mechanisms underlying decarboxylation and carboxylation. Our calculated free energies are consistent with available experimental kinetics data. Finally, we explored how different rotamers of catalytic residues influence the efficiency of the initial intermediate formation.